This invention relates to novel compounds which can inhibit angiogenesis, i.e. which can inhibit the generation or maturation of new blood vessels. It is believed that said compounds may be beneficial in the treatment of a variety of diseases, such as atherosclerosis, inflammatory conditions such as dermatitis, psoriasis, rosacea and rheumatoid arthritis, eye diseases such as diabetic retinopathy and macular degeneration as well as cancer.
It is now widely accepted that blocking angiogenesis around tumours could be a viable way of treating cancer, possibly as an adjuvant treatment. This is also reflected in the large number of development projects and clinical trials with angiogenesis inhibitors with different inhibitory approaches. There are 5 launched drugs and more than 30 agents in development that aim to restrict angiogenesis by inhibiting VEGF/VEGFR signalling.
This way of blocking angiogenesis is of particular interest for the present invention, which relates to VEGF receptor inhibitors, most particularly VEGFR-2 (KDR) receptor inhibitors. Sorafenib and Sunitinib were both launched in 2006 and both target, amongst others, VEGFR-2. Sunitinib inhibits VEGFR-2 and PDGFR-β with IC50 values of 9 and 8 nM respectively. Whilst the developers of Sorafenib have concentrated on improving its activity against Raf-1 kinase, it also exhibits an IC50 of 22 nM for VEGFR-2. Kiselyov et al. have reviewed such inhibitors in clinical trials in Expert Opin. Investig. Drugs (2007) 16(1):83-107.
A number of studies have been carried out investigating the role of VEGF and its receptors VEGF-R1 and VEGF-R2 in skin diseases such as rosacea. Rosacea is a common chronic condition affecting mainly the facial skin and characterised by visible blood vessels, central facial erythema and often papules and pustules. The pathogenesis of the disease has not been fully explained, but a link, especially in the case of non-phymatous rosacea, with VEGF has been suggested by Smith J R et al. [Br J Opthalmol 2007; 91:226-229] and Gomaa A H A et al. [J Cutan Pathol 2007; 34:748-753]
There is also clear evidence to suggest that increased expression of angiogenic factors, in particular VEGF, is a central cause of proliferative diabetic retinopathy (PDR). In this condition, and others such as retinopathy of prematurity, sickle cell retinopathy, age-related macular degeneration, retina vein occlusion and Eales disease, preretinal vascularisation is a major cause of blindness. New blood vessels grow from the inner retinal vasculature into the vitreous humour. This can cause visual loss by vitreous haemorrhage and/or tractional retinal detachment due to contraction of the fibrous tissue associated with the new blood vessels. Recently, pharmaceutical companies have been investigating drug targets to inhibit the angiogenic pathways, with TG100801, which inhibits both VEGFR-2 and Src kinases currently in clinical trials for the treatment of age-related macular degeration. Other inhibitors of the VEGF pathway intended to treat eye disease are discussed by Slevin et al. in Expert Opin. Investig. Drugs (2008) 17(9):1301-1314.
WO 01/29009 and WO 01/58899 describe pyridine derivatives as inhibitors of the VEGF receptor tyrosine kinase and the VEGF-dependent cell proliferation.
WO 02/090346 describes phthalazine derivatives as inhibitors of the VEGF receptor tyrosine kinase with angiogenesis inhibiting activity.
WO 04/056806 teaches 2-(1-H-indazol-6-ylamino)-benzamide compounds as protein kinases inhibitors which may be useful for the treatment of ophthalmic diseases.
PCT publications WO 00/27819, WO 00/27820, WO 01/55114, WO 01/81311, WO 01/85671, WO 01/85691, WO 01/85715, WO 02/055501, WO 02/066470, WO 02/090349, WO 02/090352, WO 03/000678, WO 02/068406, WO 03/040101, and WO 03/040102 all teach anthranilic acid amide derivatives which include compounds of general structure A, their preparation and their use as VEGF receptor tyrosine kinase inhibitors for the treatment of diseases associated with VEGF-dependent cell proliferation.

The use of anthranilic acid amide derivatives for other therapeutic purposes have previously been disclosed in, e.g. U.S. Pat. No. 3,409,688 (analgesic, anti-inflammatory, anti-ulcer), and in EP 564,356 (angiotensin II antagonist).
PCT publications WO 02/06213 and WO 99/01426 teach substituted phenylamino benzhydroxamic acid derivatives which include compounds of general structure B as MEK inhibitors, pharmaceutical compositions and methods of use thereof.

U.S. Pat. No. 5,155,110 teaches hydroxamic acid derivatives having cyclooxygenase and 5-lipoxygenase inhibiting properties and pharmaceutical compositions for treating conditions advantageously affected by the inhibition. The reference fails to describe tyrosine kinase inhibitory activity of the hydroxamic acid ester derivatives disclosed.
WO 05/054179 describes hydroxamic acid ester derivatives having the general structure C as angiogenesis inhibitors that act by inhibiting VEGF receptors, in particular VEGFR-2 (KDR) receptors.

It is further envisaged that compounds of the present invention may be useful as inhibitors of other kinases such as protein tyrosine kinases of the Src family such as Src, Yes, Fyn, Lyn, Fgr, Lck and/or Hck, and/or JAK-2, and/or Raf-1, and/or cKit, and/or Fma/CSF-1R protein tyrosine kinases and as such show utility in the treatment of inflammatory and non-infectious autoimmune diseases wherein these kinases are involved.
Protein tyrosine kinases are a family of enzymes catalysing the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. Phosphorylation of tyrosine residues on protein substrates leads to transduction of intracellular signals which regulate a wide variety of intracellular processes such as growth and activation of cells of the immune system, e.g. T-cells. As T-cell activation is implicated in a number of inflammatory conditions and other disorders of the immune system (e.g. autoimmune diseases), modulation of the activity of protein tyrosine kinases appears to be an attractive route to the management of inflammatory diseases. A large number of protein tyrosine kinases have been identified which may be receptor protein tyrosine kinases, e.g. the insulin receptor, or non-receptor protein tyrosine kinases.
Protein tyrosine kinases of the Src family have been found to be particularly important for intracellular signal transduction related to inflammatory responses (cf. D. Okutani et al., Am. J. Physiol. Lung Cell Mol. Physiol. 291, 2006, pp. L129-L141; C. A. Lowell, Mol. Immunol. 41, 2004, pp. 631-643). While some of Src family protein tyrosine kinases, e.g. Src, Yes and Fyn, are expressed in a variety of cell types and tissues, the expression of others is restricted to specific cell types, e.g. hematopoietic cells. Thus, the protein tyrosine kinase Lck is expressed almost exclusively in T-cells as the first signalling molecule to be activated downstream of the T-cell receptor, and its activity is essential for T-cell signal transduction. Expression of Hck, Lyn and Fgr is increased by inflammatory stimuli such as LPS in mature monocytes and macrophages. Also, if gene expression of the main B-cell Src family kinases, namely Lyn, Fyn and Blk, is disrupted, immature B-cells are prevented from developing into mature B-cells. Src family kinases have also been identified as essential for the recruitment and activation of monocytes, macrophages and neutrophils as well as being involved in the inflammatory response of tissue cells. For example, it has been found that expression of Hck, Lyn and Fgr is increased by inflammatory stimuli such as LPS in mature monocytes and macrophages.
A substantial number of autoimmune and inflammatory diseases involve the activation of T-cells and B-cells as well as other cells of the immune system such as monocytes and macrophages. Compounds which are capable of inhibiting activation of these cell types are therefore regarded as useful therapeutic agents in the treatment of such diseases.